Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. Ifosfamide is the drug whose chemical name is 3-(2-chloroethyl)-2-[(2-chloroethyl amino)]-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide. It belongs to a group of chemical compounds denoted oxazaphosphorines, which are presently in use as therapeutic agents for the treatment of tumors. Ifosfamide is presently used in combination with certain other antineoplastic agents, and is a third line chemotherapeutic for the treatment of testicular cancers derived from germ cells. Generally, it is used in conjunction with a hemorrhagic prophylactic agent, such as mesna.
The solubility of ifosfamide is about 10% by weight in water, the aqueous solutions only being of limited shelf-life at room temperature. Ifosfamide solutions are administered parenterally at a maximum concentration of the aqueous solution of 5% (50 mg/mL).
It is desirable to provide a ready-to-use stable aqueous ifosfamide composition that could be administered without the need for reconstituting ifosfamide sterile powder currently available or a lyophilized ifosfamide composition. However, an impediment to the preparation of an aqueous ifosfamide composition is that such compositions may not be adequately stable at ambient temperatures. Generally, ready-to-use solutions are stored and transported at refrigerated temperatures (e.g., 2° C.-8° C.) to circumvent the lower stability of ready-to-use solutions in comparison to powder or lyophilized compositions. Still, accidental exposure of a ready-to-use ifosfamide composition to elevated temperatures (i.e., temperatures at or above ambient temperature) during storage or transportation can result in unacceptable levels of degradation.
An object of the present invention is to provide a ready-to-use aqueous ifosfamide composition with enhanced stability at elevated temperatures such that accidental exposure of the composition to elevated temperatures for a brief time would be less likely to result in unacceptable levels of degradation of the ifosfamide.